Treatment of glaucoma employing imipramine or desmethylimipramine

ABSTRACT

GLAUCOMA IS TREATED WITH COMPOSITIONS CONTAINING DESMETHYLIMIPRAMINE OR IMIPRAMINE OPTIONALLY IN THE PRESENCE OF AN ALKYL GALLATE AND/OR A SYMPATHETIC OR SYMPATHOMIMETIC AMINE. A TYPICAL EMBODIMENT IS AN OPHTAHLMIC PHARMACEUTICAL COMPOSITION CONTAINING DESMETHYLIMIPRAMINE AND EPINEPHRINE.

United States Patent 3,705,942 TREATMENT OF GLAUCOMA EMPLOYING IMIPRAMINE 0R DESMETHYLIMIPRAMINE Edgar Grunwaldt, New York, N.Y., assignor to Ciba-Geigy Corporation, Ardsley, N.Y. No Drawing. Filed Sept. 29, 1969, Ser. No. 862,054 .Int. Cl. A61k 27/00 U.S. Cl. 424244 7 Claims ABSTRACT OF THE DISCLOSURE Glaucoma is treated with compositions containing desmethylimipramine or imipramine optionally in the presence of an alkyl gallate and/or a sympathetic or sympathomimetic amine. A typical embodiment is an ophthalmic pharmaceutical composition containing desmethylimipramine and epinephrine.

DETAILED DESCRIPTION JH CH CHPN wherein R is hydrogen or methyl, or an ophthalmically acceptable salt thereof, effects pupillary dilation and a decrease in intraocular pressure when topically administered to the eye. These compounds include imipramine and desmethylimipramine, both well known as antidepressant agents.

The compound is preferably administered in form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye, such as solutions and ointments. If necessary, solubilizing agents suitable for the treatment of eyes are added. Such solubilizing agents include propylene glycol, polyethylene glycol, polysorbate 80 and poloxalene. It is advantageous to add preservatives compatible with the ingredients and non-irritating to the eye. Such preservatives include merthiolate, phenyl mercuric acetate, benzalkonium chloride and phenylethanol. It is also advantageous to use a buffered solution of a pH between and 7, preferably about 6. Suitable buffers include borate, phosphate, and acetate buffer systems.

A further embodiment of the present invention is the topical administration of compounds of Formula I in combination with an alkyl gallate and/or a sympathetic or sympathomimetic amine. Suitable alkyl gallates are esters of gallic acid with an alkanol of from 1 to 9 carbon atoms. Suitable sympathetic or sympathomimetic amines are epinephrine, norepinephrine, phenylephrine and the like. A preferred embodiment of the present in- Patented Dec. 12, 1972 vention is the combined administration of desmethylimipramine and epinephrine.

Generally, a compound of Formula I will be present in such compositions in an amount of from about 0.01% to about 1%, preferably from about 0.1% to about 0.5%.

These compositions can in addition contain from about 0.1% to about 2%, preferably from about 0.5% to about 1% of an alkyl gallate and/or a sympathetic or sympathomimetic amine.

Preparation and use of different dosages concentrations permits greater flexibility for treatment since factors such as the age of the individual and the severity of particular conditions can be taken into consideration. The actual dosage administered is adjusted to the need and depends upon the response elicited, with observance of the usual precautions indicated by sound professional practice.

The compositions are particularly useful in the treatment of chronic simple glaucoma in pre-presbyopic cases, chronic simple glaucoma in the presence of cataracts, and secondary glaucoma with active uveitis.

The term ophthalmically acceptable salt thereof as used herein and the appended claims includes those salts derived from organic and inorganic acids which are not irritating to the eye. Illustrative of such acids are, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, ethane disulfonic, acetic, citric, malic, succinic, lactic, tartaric, benzoic, phthalic, pamoic, fumaric, maleic, and the like.

The term fluid carrier includes water, lower molecular polyethyleneglycols, 1,3-butylene glycol, diethylene glycol, dipropylene glycol, glycerin, tri-isopropyl phenyl phosphate. More carriers suitable for ophthalmic use are described in Am. Journ. of Ophthomology, vol. 29, p. 1363-1372 (1946).

The following examples serve to illustrate the invention without limiting same thereto.

EXAMPLE 1 A topical solution of 0.25% desmethylimipramine is prepared by dissolving an appropriate quantity in sterile water, maintaining aseptic conditions throughout the preparation. The solution is sterilized by bacteriologic filtration and filled into sterile glass dropper bottles. This solution is administered topically by dropping appropriate quantities into the eye.

A similar solution can be obtained with 0.5 of imipramine.

EXAMPLE 2 A sterile aqueous solution of 0.1% of desmethylimipramine and 0.5% of butyl gallate is prepared according to Example 1 for topical use.

A similar solution can be obtained by using 0.25 of desmethylimipramine and 0.5 of butyl gallate.

EXAMPLE 3 The following gallates, all of which are known or can be synthesized readily by techniques familiar to those skilled in the art, are converted to dosage forms analogous to those of Examples 1 and 2:

methyl gallate ethyl gallate propyl gallate isopropyl gallate octyl gallate nonyl gallate In the case of insolubility in water, a solubilizing agent such as polyoxyethylene ricinoleate is used.

A similar solution can be obtained by using 0.2% of imipramine and 0.5% of epinephrine.

EXAMPLE A solution was prepared from the following compounds:

Percent Desmethylimipramine 0.50 Butyl gallate 1.00

Pluronie F-68 (oxyethyleneoxypropylene) polymer 15.00 Phenylethanol 0.25 Benzalkonium chloride 0.02 Acetic acid 0.05 Sodium acetate 2.00 Disodium EDTA 0.05 Sodium bisulfite 0.10

Water, distilled q.s., 100.00%.

In preparing the solution, the pluronic R68 is dissolved in water before addition of the butyl gallate.

EXAMPLE 6 A solution is prepared from the following compounds for topical use:

A solution is prepared according to Example 5 incorporating 0.50% of desmethylimipramine, 0.50% of butyl gallate and 0.50% of epinephrine.

What is claimed is:

1. A method of treating glaucoma in humans through reduction of intraocular pressure which comprises topically administering to an eye having glaucoma an efiective amount of'an ophthalmic pharmaceutical composition containing from about 0.01% to about 1% of a compound of the formula:

N /CHa (EHr-CHr-CHa-N wherein R is hydrogen or methyl, or an ophthalmically acceptable acid addition salt thereof, and a fluid carrier, suitable for ophthalmic use.

2. The method according to claim 1 wherein R drogen.

3. The method according to claim 1 wherein said composition further contains from about 0.1% to about 2% of at least one member selected from the group consisting of (a) an ester of gallic acid with alkanol of 1 to 9 carbon ataoms and (b) a sympathetic or sympathomimetic amine, selected from the group consisting of epinephrine, norepinephrine and phenylephrine.

4. The method of claim 3 wherein said composition contains from about 0.1% to about 2% of butyl gallate.

5. The method of claim 3 wherein said composition contains from about 0.1% to about 2% of epinephrine.

6. The method according to claim 1 wherein said composition further contains from about 0.1% to about 1% of a mixture of an ester of gallic acid with alka-nol of l to 9 carbon atoms and from about 0.1% to about 1% of a sympathetic or sympathomimetic amine, selected from the group consisting of epinephrine, norepinephrine and phenylephrine.

7. The method of claim 6 wherein said composition contains from about 0.1% to about 1% of butyl gallate and from 0.1 to about 1% of epinephrine.

is hy- References Cited UNITED STATES PATENTS 6/1970 Biel 424-244 OTHER REFERENCES J EROME D. GOLDBERG, Primary Examiner v. D. TURNER, Assistant Examiner Us. 01. X.R. 

